ANTITUBERCULOSIS DRUG DOSAGE FORMS: RANGE, KEY BENEFITS AND PROSPECTS OF TECHNOLOGICAL IMPROVEMENT

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In the 1990-s the tuberculosis (TB) epidemic resumed and now tuberculosis is a threat to the planet’s population not less than any other infectious disease. According to the World Health Organization, there are about 1.7 million victims of this disease in the world every year, and about 5 thousand people die every day. Tuberculosis is a curable disease. Also, according to the WHO, in some parts of the world one in four people with tuberculosis develops form of the disease that does not respond to the standard long-term treatment with the first line antituberculosis (anti-TB) drugs. Currently, there is a high incidence of acquired drug resistant tuberculosis in Kazakhstan and in the Russian Federation as well. One of the reasons that contribute to the development of acquired drug resistance is an abnormality or interruption of the treatment by patients, due to the high toxicity of anti-TB drugs. Therefore, improvement of the TB treatment efficiency remains one of the most urgent issues [1-3]. The aim this study was to review the dosage forms of antituberculosis drugs currently used and the ways to improve them. Methods. The study was conducted on the basis of scientific analysis (eLibrary database, PubMed, Cyberleninca), patent (kzpatents), reference (Klifar, Drugs register) and technical literature. Results. The need to use several drugs at the same time, the availability of the spectrum of side effects of most anti-TB drugs and the duration of treatment are the specificity of treatment of tuberculosis. Therefore, the efficiency and convenience of drug administration is largely determined by a dosage form of anti-TB drugs [4]. The analysis of anti-TB drugs revealed in accordance with data of the Drug Register and the State Drug Register of the Russian Federation (electronic version), now they are represented in the following dosage forms (Table 1) [5, 6]. As seen from the table 1, anti-TB drugs are produced in the form of tablets, capsules, granules for oral use and injection solutions. The oral way is usually the most convenient, and usually the safest and least expensive. Nevertheless, disadvantages of oral way are delayed onset of action and development of first pass effect via the liver. Furthermore, delayed absorption in some cases is noted due to the physicochemical properties of drugs, and the influence of the contents of the gastrointestinal tract as well as other factors. In particular, antacids, particularly containing aluminum, reduce the absorption of isoniazid and ethambutol. When receiving therapeutic doses of ethionamide, significant variations are marked in the blood concentration, which are caused by a different condition of secretory and motor function of the intestine, its degree of filling of edible mass, etc. Concomitant intake of fatty foods increases the degree of absorption of p-aminosalicylic acid [6, 7]. The range of anti-TB drugs in the regional pharmaceutical markets, according to market researches, includes mainly solid dosage forms (tablets, capsules) up to 75%. Tablet dosage forms are preferable (according to the literature, they are 96.2% of the respondents preferences) in connection with the duration of administration of this group of drugs [8, 9]. Among tablet forms it is necessary to allocate film-coated tablets. The main purpose of coating is the masking of the specific taste of certain drugs, and reduction of the incidence of side effects. For example, the use of ethionamide tablets without coating results in dyspepsia in almost 90% of cases. At the same time the intake of ethionamide coated tablets, according to the literature, helps to reduce the frequency of dyspeptic disorders and provides long-lasting blood levels of the drug [4, 10]. A disadvantage of film-coated tablets (protionamid), which are usually without a score line, is the inability to evenly divide a tablet into parts, when it is necessary to use them in pediatric practice, and that can ultimately lead to dosing inaccuracies [4]. Also, the inability to ensure dosing accuracy when using drugs for adults and pediatric patients is observed for such a dosage form of anti-TB drugs as capsules (eg. cycloserine, only dosage for adults are manufactured abroad) [4]. Difficulties with dosing accuracy are marked for anti-TB drugs in pellets. At the same time this form has advantages, among which we should highlight the possibility of a prolonged effect achieving [4, 11]. The use of combined tablet anti-TB drugs, especially in the outpatient stage of treatment promotes the improvement of efficiency of treatment: a patient takes a smaller amount of finished dosage forms, including due to the synergy of active ingredients, and gets drugs in a rational combination. International Union Against Tuberculosis and Lung Diseases in its recommendations on chemotherapy deems it expedient to use combinations of drugs in fixed doses, because this approach eliminates the monotherapy and dosing inaccuracies. The combined anti-TB drugs are convenient for patients and medical staff and they are considered a reliable method of controlled therapy. And the opportunity to prevent drug resistance when used combined therapy drugs is noted as their greatest advantage [7, 12, 13]. In fact anti-TB drugs, as well as combinations, containing isoniazid with vitamin (pyridoxine) are produced in the form of combined tablets. Long intake of a large number of anti-TB drugs often leads to a refusal of patients from treatment or violations of intake conditions due to concomitant adverse toxic reactions (eg, isoniazid), which are one of the causes of multidrug resistance. Isoniazid combinations with vitamin B are used to reduce its toxicity [6]. Disadvantages of combined preparations include rigidly fixed doses, which are not capable of changing a concentration if necessary, the asynchrony of onset of effect, the inability to multi-directional combination with food. Furthermore, it should be noted certain difficulties in the development of technology: the provision of bioavailability of all the components of the composition, the provision of a combination of all the components in the combined tablets, certain features of the technology caused by the need of selection of suitable conditions of tableting for all components [13, 14]. Therefore, the actual problem remains the development of the tablets which are free from these disadvantages, for example, orodispersible (dispersible, “soljutab” form). Orodispersible tablets are tablets or porous mass in the form of tablets, disintegrating or dissolving in the mouth in less than three minutes without taking water. Their advantages are as follows: the increase of drug absorption, minimization of the first stage of absorption, the increase of safety and efficiency, along with the possibility of longterm storage due to solid tablet form. Furthermore, there are a number of advantages of using the dispersible tablets directly to the patient: the tablets are easier to swallow, it is not necessary to drink water, i.e. they can be taken without water at any place at any time. All this offers the possibility to use them for children, the elderly and other groups of patients who have difficulty with conventional oral administration of drugs [15, 16]. ] Recently dispersible tablets are considered as an alternative to suspensions, syrups and conventional tablets to enhance the effectiveness of antibiotic therapy, particularly tuberculosis. A feature of the dispersible tablets is the incorporation as active substance in microparticles to protect it from adverse effects of the acidic environment of the stomach and enzymes. A partial absorption of drugs from the dispersible tablets in the mouth makes it possible on some extent to avoid the effect of “primary” drug passing through liver. Drugs in this form also possess additional advantages in low incidence of microbial resistance to them, because they are characterized improved pharmacokinetic properties [16]. Researches on the development of oral dispersible tablets of anti-TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide) are carried out in PhC “Romat” (Kazakhstan). During the pre-clinical safety studies of drugs Ethambutol-D, Isoniazid-D (orally disintegrating tablet), their distinctive advantages were proved: minimization of the first stage of absorption due to dissolution of the drug in the mouth and the adsorption from the saliva, the increase of the adsorption rate, the rise of the total bioavailability, the improvement of safety and efficacy [17, 18]. Evaluation of the clinical efficacy of the drug Isoniazid-D and Ethambutol-D in the National Center for Tuberculosis Problems (Republic of Kazakhstan) showed the feasibility of using drugs in the treatment of newly diagnosed pulmonary tuberculosis [3]. According to data of clinical studies, when Isoniazid-D and Ethambutol-D in the form of dispersible tablets are used, a prominent therapeutic effect happens: the disappearance of symptoms of intoxication, the conversion of smear, good tolerability and a positive X-ray dynamics in the form of re- sorption of infiltration and sealing lesions, the decrease of destructive changes in size [19]. One of alternative oral dosage forms are oral liquid forms: syrups, solutions and suspensions. These dosage forms provide a more comfortable administration than conventional tablet forms, they possess greater bioavailability, corrected taste [20, 21]. As an example, isoniazid syrup 100mg / 5ml, which is produced in Ukraine and exported to the CIS countries (Azerbaijan, Georgia, Kazakhstan, Uzbekistan, Moldova and others.). According to the manufacturer, the use of isoniazid in the form of a syrup is indicated for children as well as adults, suffering from TB, with concomitant diseases of the digestive system (gastritis, gastric ulcer, etc.). Due to the accuracy of dosing, less irritating effect on the digestive organs, as well as a pleasant taste and smell, the use of isoniazid in the form of a syrup let you carry out prevention and treatment of tuberculosis conveniently and safely [22]. As another example of liquid forms of anti-TB drugs it can be noted a suspension of moxifloxacin, prepared extemporaneously, which makes it possible to use a more accurate dosing and give the drug to children. However, it is noted that the preparation of this form requires a certain level of learning and resources (purified water), which may be absent in many countries and regions. Extemporaneously prepared suspension is still a form far from an ideal one, therefore the production of industrial forms such as a pediatric form - oral solution of Levofloxacin, 25mg / mL, produced in the US, is encouraged [4]. The second frequent way of the administration is a parenteral one, it has the highest bioavailability and eliminates the first pass effect through the liver and exposures of the factors of the gastrointestinal tract. Furthermore, this way provides a control of the actual dose of administered drugs. However, parenteral administration is often perceived as a painful way of administration, which is aggravated by the fact that the course of treatment with anti-TB drugs is long (up to 6 months), it causes discomfort to the patient, as well as additionally requires the presence of medical staff [7, 23]. For such anti-TB drugs as isoniazid, rifampicin, PAS, the injection way is an alternative to oral administration. But, for example, amikacin, like other antibiotics - aminoglycosides, is not administrated orally, since the drugs are not absorbed from the gastrointestinal tract. Amikacin is produced in the form of powder for injection, and solution for injection, the latter is more comfortable because it does not require dissolution of the powder [4]. Another way of administration of anti-TB drugs, which is hardly used but quite promising, is a rectal method of administration. It makes it possible to carry out the therapy when oral administration of anti-TB drugs is not possible. There are findings that the administration of 0.5 g ethionamide in forms of rectal suppositories has the same level as when administered in the same dos- age form of enteric tablets [10, 24]. How- ever, it has several disadvantages: it causes discomfort; it is contraindicated in diseases of the rectum. The possibility of the use of extemporaneously prepared suppositories of rifampicin is shown in clinical studies. There are findings of preclinical studies demonstrating the effectiveness of the use of rifampicin in the form of suppositories based on cocoa butter [24, 25]. There are findings of rectal use of ultra-emulsion of lecithin and a complex of anti-TB drugs of isoniazid, rifampicin, kanamycin, prepared ex temporae in combination with oral pyrazinamide and ethambutol. According to the results of clinical studies, it have been proven the high efficacy and good tolerability of the rectal way of administration ultra-emulsion of anti-TB drugs in the treatment of destructive infiltrative and disseminated pulmonary tuberculosis in newly diagnosed patients [24]. Recently an inhalation is considered as a way of administration of anti-TB drugs in the scientific literature. Drug of isoniazid solution is produced in the Russian Federation, designed for administration through inhalation as well. Inhalation therapy of pulmonary tuberculosis can be carried out as an optional chemotherapy for the back- ground chemotherapy [7, 24]. It is believed that aerosol therapy is contraindicated in pulmonary tuberculosis, since it can provoke pulmonary hemorrhage. It may be noted the advantages of modern inhalation aerosol therapy, in which the anti-TB drugs can enter directly into the lungs as a target organ, bypassing the long way of delivery. According to opinions of some authors, the use of modern nebulizers allows to carry out the therapy in dose-spar- ing regime and provide the delivery of up to 70% of particles to the lungs [27]. There are findings of in vivo studies on the improvement of the efficiency of the directional inhalation exposure to various antituberculous immobilized drugs in the composition of liposomes, niosomes, nanocapsules, micelles, micro- and nanoparticles. The use of immobilized anti-tuberculosis drugs offers the protection of the drug against the metabolism in the lungs and prolonged drug release [28]. The use of microparticles with sustained release will reduce the frequency of the use of anti-TB drugs and their dosage, reduce side effects associated with long-term oral anti-tuberculosis therapy. Moreover, the drug microparticles can effectively penetrate into the pulmonary alveoli, and may then generate high intracellular drug concentrations in lung macrophages, where mycobacteria are concentrated [28, 29]. There are findings about detection of anti-TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) when administered in the form of nanocapsules and nanoparticles for a long time in comparison with the free form of drugs in animal studies [28]. Interest in molecular encapsulation of medicinal substances with cyclodextrins is enhanced, in connection with a possible increase in the bioavailability of the active ingredients, the reduction the harmful effects on the gastrointestinal tract, the possibility of extension, elimination of interaction of incompatible components in combined preparations, the protection of unstable substances on exposure to light and moisture, as a proven result of pre-clinical studies. So, studies of the possibility of incorporation of cyclodextrin in rifampicin and pyrazinamide showed prominent antibacterial activity of the complex, due to the increased ability to penetrate the mycobacterial cells. There is also evidence of the possibility of reduction of the toxicity of isoniazid via encapsulation with cyclodextrins [17, 30]. Conclusion. Thus, the modern anti-TB drugs are mainly presented by dosage forms: oral (tablets, capsules, syrups and suspensions) and injectable. Rectal suppositories are considered as a promising form. The main goals in improving drug anti-TB drugs are the reduction of toxicity, the improvement of the drug intake comfort, the rise of bioavailability and efficacy of treatment. This can be realized, including expansion of the product range of oral liquid forms, tablets, orally dispersible, the use of innovative technologies (incorporation of drugs in the form of nanoparticles, micro- and nanocapsules, liposomes).

About the authors

M. E Kim

Ph C “Romat”

Email: company@romat.kz
Republic of Kazakhstan, Pavlodar city

K. B Murzagulova

Ph C “Romat”

Email: vpn@romat.kz
Republic of Kazakhstan, Pavlodar city

E. F Stepanova

Russia, Pyatigorsk

Email: e.f.stepanova@mail.ru

References

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